Prevalence of Ocular Anomalies in Craniosynostosis: A Systematic Review and Meta-Analysis

Background: The aim of this study was to describe the ophthalmic abnormalities and their prevalence in craniosynostosis prior to craniofacial surgery. Methods: A systematic search was conducted on Medline OVID, Embase, Cochrane, Google Scholar, Web of Science Core Collection. Inclusion criteria were English papers, children aged <18 years with non-syndromic and syndromic craniosynostosis, case reports, case series, and case-control studies. A system of domains was established consisting of an anatomic and functional ophthalmic domain. A meta-analysis of single proportions was carried out using random effects model and pooled mean proportions with 95% confidence intervals (CI) were calculated. Results: Thirty-two papers analyzing 2027 patients were included. Strabismus was the most common anomaly in non-syndromic craniosynostosis: Horizontal strabismus was highest prevalent in unicoronal craniosynostosis (UCS) 19% (95% CI 9–32), followed by vertical strabismus 17% (95% CI 5–33). In syndromic craniosynostosis, horizontal strabismus was most prevalent in Crouzon syndrome 52% (95 CI 26–76), followed by Apert syndrome 50% (95% CI 42–58). Vertical strabismus was most prevalent in Saethre-Chotzen 60% followed by Muenke’s syndrome 36%. Furthermore, astigmatism was the second most reported outcome in non-syndromic craniosynostosis and highest prevalent in UCS 35% (95% CI 21–51). In syndromic craniosynostosis, astigmatism was most frequently seen in Crouzon syndrome 43% (95% CI 22–65), followed by Apert syndrome 34% (95% CI 14–58). Moreover, in syndromic craniosynostosis, 5–40% had a decrease in visual acuity (VA) ≤ 0.3 LogMAR in the better eye and 11–65% had a VA ≤ 0.3 LogMAR in at least one eye. Discussion: This review demonstrates the high prevalence of ocular anomalies in non-syndromic and syndromic craniosynostosis. A multidisciplinary and systematic approach is needed for the screening and optimal treatment of these conditions in a timely manner.


Introduction
Craniosynostosis is a congenital craniofacial disorder with a prevalence of 3.1-6.4 per 10,000 live births worldwide [1][2][3][4][5]. Craniosynostosis is defined as premature closure of one or more cranial sutures. It may occur as an isolated finding or as part of a syndrome [1,6]. Isolated craniosynostosis mainly involves a single suture, and includes, in descending order of frequency, sagittal, metopic, unicoronal and lambdoid craniosynostosis [6]. It can be classified as syndromic when craniosynostosis is in combination with the presence of additional clinical symptoms, such as Apert syndrome, Crouzon syndrome, Muenke syndrome and Saethre-Chotzen. Syndromic craniosynostosis account for 15-40% of the total cases of craniosynostosis [7]. In syndromic craniosynostosis, the coronal (unicoronal

Materials and Methods
This systematic review was carried out according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [15]. Additionally, the performed systematic review was registered prospectively in the International prospective register of systematic reviews, PROSPERO with the following registration number: CRD42021249963.

Eligibility Criteria
Inclusion criteria: studies on humans, papers written in English, children with nonsyndromic or syndromic craniosynostosis of which ophthalmic examinations were available prior to craniofacial surgery, children aged <18 years, descriptive studies such as case reports, case series and randomized controlled trials, furthermore cohort studies and casecontrol studies were included. No distinction was made in ethnicity or gender. Exclusion criteria: cross-sectional studies, systematic reviews, and meta-analysis.

Information Sources and Search
A comprehensive search was performed by using MedLine Ovid, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar. The databases were searched from their respective until December 2021. The full search is demonstrated in the Supplementary Material A.

Study Selection
Firstly, two reviewers (P.R. and Z.A.) independently reviewed the title and abstract of all records to select all relevant studies. Secondly, full text of the selected studies were read and assessed independently by the two reviewers (P.R. and Z.A.) for meeting the eligibility criteria. Thirdly, P.R. and Z.A. both checked the reference list to see if there were additional relevant references. The program Endnote X9 was used for the references.

Data Collection Process and Data Items
Data were extracted from the included studies. One author extracted relevant data from each study and another author independently checked all data. Data extraction included: general information about the paper, country, setting, year, participant characteristics, method of diagnosis of ocular anomalies.

Classification of Ocular Anomalies and Orbital Malformations
In order to analyze the ocular anomalies, a system of domains was created. The ocular anomalies were categorized in two domains, namely (1) an anatomic and (2) a functional ophthalmic domain. Anatomic anomalies were defined as anatomical or adnexal anomalies that impair or are likely to impair the vision. Functional anomalies were defined as functional ocular anomalies that impair the vision.

Risk of Bias
The risk of bias was assessed using a JBI critical appraisal tool for case studies modified for this study. The following domains were assessed: inclusion criteria, validity of identification of the condition, reliability of the method of measuring, consecutive inclusion, reporting of demographics, reporting of clinical information, confounding factors, appropriate statistical analysis. Each of the above-mentioned items was assessed with yes, no, or unclear. If the study met the criteria, two points were given to that item, and it was defined as low risk of bias. If the study did not meet the criteria, or it was unclear, 0 or 1 points were given. The points for each item were added up, resulting in a total score. Studies with a total score of at least 17 points were rated as low risk of bias. A total score of twelve to seventeen points were rated as medium risk of bias, while studies which scored below 12 points were rated as high risk of bias. Studies were not excluded a priori based on quality reporting assessment.

Statistical Analysis
Descriptive statistics were used for the prevalences. Prevalences of ocular anomalies were extracted or calculated from the available data. The total number of ocular and orbital anomalies were divided by the total sample size of each specific disorder and were presented as (n = %). A meta-analysis of single proportions was carried out using the random effects model for the differrent ocular anomalies, and pooled mean proportions with 95% CI's were calculated. A p value of <0.05 was defined as statistically significant. Data was converted using the Freeman-Tukey double arcsine transformation, to modify for the small sample sizes and possibly extreme proportions. Heterogeneity was evaluated by the I 2 statistics [16]. The software program R version 4.1.2. for windows was used for the meta-analysis and forest plots. The GRADE certainty rating was used for evaluation of quality of evidence [17]. This consisted of risk of bias, inconsistency, indirectness, imprecision and publication bias [17].

Results
The literature search retrieved 3923 papers. After deduplication, 2611 papers were screened for eligibility. Of these, 2458 papers were excluded after 'Title and Abstract' (TiAb) screening. Hundred-two papers were available for full-text screening, of which eight papers had no access to full-text, six were not written in English and another 56 papers did not meet our inclusion criteria. In most of the excluded papers, ophthalmic examinations prior to craniofacial surgery were not described, or it was unclear if the patients had any craniofacial surgery prior to the ophthalmic examinations. Furthermore, other papers were excluded because the patients were older than 18 years old, or the outcome measurements were not based on ocular or orbital abnormalities. Thirty-two papers were eligible for inclusion and were included in the qualitative analysis. The detailed information of the record selection process is shown in Figure 1. Of the 32 papers included, 11 papers focused on non-syndromic craniosynostosis, 16 papers focused on syndromic craniosynostosis and five papers included both groups. The studies had no overlap in patients. The included studies were published between 1987 and 2021. The sample size ranged from 5 to 205 patients. A total of 2027 patients were included for analysis in this systematic review. In Table 1 the characteristics of the included studies are presented. In total 28 papers were included in the quantitive analysis. Four papers were excluded from the quantitative analysis, because they did not indicate the exact sample size per disorder. All meta-analysis and forest plots are demonstrated in the Supplementary Material B.

Syndromic Craniosynostosis
All functional ophthalmic anomalies in syndromic craniosynostosis are presented in Table 5. Strabismus was the most reported anomaly consisting of horizontal (esotropia and exotropia) and vertical (hypotropia and hypertropia) strabismus with a prevalence of 58% (n = 445; 95% CI 41-73) [27,28,33,35,37,[43][44][45][46]. Exotropia was most commonly reported in Crouzon syndrome with a prevalence of 47% (n = 197; 95% CI 18-77) [27,37,[43][44][45], followed by Apert syndrome 38% (n = 128; 95% CI 27-50) [35,[43][44][45]. Hypertropia was most prevalent in Saethre-Chotzen with a prevalence of 60%, followed by Muenke syndrome 36% [28]. Among refractive errors, astigmatism was the most reported outcome, and highest prevalent in Crouzon 43% (n = 136; 95% CI 22-65) [27,[43][44][45], followed by Apert with a prevalence of 34% (n = 128; 95% CI 14-58) [35,[43][44][45]. Ptosis was most prevalent in Saethre-Chotzen (90%), followed by Muenke syndrome (36%) [28]. Other ocular anomalies reported were nystagmus with a prevalence of 12% in Crouzon and the same study also reported blindness in 7% of the cases, whereas 46% of the other children had a poor vision in at least one eye [37].  Figure 2 and Table 1. Present the assessment of risk of bias for the included studies. In total, six studies (19%) were evaluated as high risk of bias, ten studies (31%) were evaluated as medium risk of bias and 16 studies (50%) were assessed as low risk of bias. In most studies, a different method of ophthalmic examinations and diagnosis was used. Therefore, a high risk of confounding and performance bias was found in most studies. In total, 71% of the studies reported the method of ophthalmic examination and diagnosis. Therefore, the validity of diagnosis of the different anomalies was rated as low risk. The reliability of method of examination and diagnosis was evaluated as medium to high risk of bias in 26% of the studies. Demographics and clinical information were evaluated as low risk of bias, as most studies reported demographics such as age, gender, clinical situation at the moment of examination, medical history. Three studies did not define the demographics and were rated as high risk [24,36,37]. The included studies had a good representative population of the target population, most studies only evaluated syndromic or non-syndromic craniosynostosis, however some of these studies evaluated them together [18,20,21,25,47]. This often meant that the study population was larger, and therefore the prevalence's were stated differently than if you compared each group with itself. Furthermore, not every study reported whether genetic analysis was performed to diagnose syndromic craniosynostosis, while this is officially necessary for establishing this diagnosis. Finally, for systematic reviews describing prevalence's of rare diseases, it is difficult to take action on risk of bias. As sometimes it can be misleading to rate a study as low or high risk based on a previously compiled checklist, as some biases can be more valuable than others. Conclusively, the study by Hoy et al., 2012 indicates that the assessment of risk of bias provides invaluable information in the description of outcomes in systematic reviews of disease prevalence [48]. For these reasons, papers with high risk of bias were not excluded from the qualitative analysis.

Risk of Bias
is difficult to take action on risk of bias. As sometimes it can be misleading to rate a study as low or high risk based on a previously compiled checklist, as some biases can be more valuable than others. Conclusively, the study by Hoy et al., 2012 indicates that the assessment of risk of bias provides invaluable information in the description of outcomes in systematic reviews of disease prevalence [48]. For these reasons, papers with high risk of bias were not excluded from the qualitative analysis.

GRADE Certainty Rating
The meta-analysis included 23 separate analyses, which are demonstrated in the Supplementary Material B. Heterogeneity was considered low (<40%) in five analysis. This included horizontal strabismus in Apert syndrome I 2 = 0%, p = 0,47, papilledema in Apert syndrome I 2 = 11%, p = 0.35 and after exclusion of outliers I 2 = 0%, p = 0.85, esotropia in UCS I 2 = 16%, p = 0.31, and anisometropia in UCS I 2 = 29%, p = 0.24. Heterogeneity was considered moderate (30-60%) in five analyses. This included astigmatism in UCS I 2 = 54%, p = 0.11, papilledema in non-syndromic craniosynostosis I 2 = 51%, p = 0.11, esotropia in UCS I 2 = 50%, p = 0.09, exotropia in UCS I 2 = 43%, p = 0.13, and exotropia in Apert syndrome I 2 = 33%, p = 0.23. In the other 13 analysis, heterogeneity was considered high (65-100%) and statistically significant (p < 0.01). Conceivably caused by differences in patient characteristics or method of ophthalmic examination. Directness was considered high, as most studies directly investigated ocular anomalies in the target population. Imprecision cannot be ruled out due to the relatively small sample sizes and consequently wide confidence intervals. Furthermore, due to the small sample sizes and the rarity of craniosynostosis, it is difficult to draw a conclusion about publication bias. In addition, the meta-analysis was divided over the different ocular anomalies, so that the scatter plots cannot be officially used to indicate symmetry for publication bias. However, the study of Abboud et al., 2020 [19], was suspected of publication bias. As they reported a high prevalence of papilledema (67%) in lambdoid craniosynostosis, without further explanation. Finally, no exact conclusions can be drawn, as this grading is subjective, however, we rate the GRADE certainty rating as moderate.

Discussion
This systematic review is the first to report on the prevalence of pre-operative ocular anomalies in both non-syndromic and syndromic craniosynostosis in a systematically order. In order to systematically analyze the ocular anomalies, a system of domains was created by our workgroup. All ocular anomalies were subdivided into either an (1) anatomic ophthalmic domain or (2) a functional ophthalmic domain. Anatomic anomalies were defined as anatomical or adnexal anomalies that impair or are likely to impair the vision. Functional anomalies were defined as functional ocular anomalies that impair the vision. Current literature often used the ocular terms interchangeably throughout the papers and often there was no structure. This division has contributed to provide a more structured overview of the various ophthalmic abnormalities present in the patients. It must be noted that this is not an official classification and this classification was used because no previous classification system could be identified. Our study confirmed that ocular problems are highly prevalent in craniosynostosis.
Due to the rarity of craniosynostosis and the small numbers of patients in most studies, there are no clear guidelines in regard to age of screening, screenings technique and optimal time of ophthalmic treatment per disorder. There are currently few studies that have examined the ocular function pre-and postcraniofacial surgery. In a recent published prospective study of Ntoula et al., 2021 [38], 122 patients with non-syndromic craniosynostosis were examined pre-and postoperatively. They concluded that patients with sagittal craniosynostosis show a low prevalence of ocular anomalies, and therefore do not need to have a routine ophthalmic examination pre-operatively, and patients are advised to have ophthalmic examination postoperatively. However, they do advise patients with unicoronal and metopic craniosynostosis to have both pre-and postoperative ophthalmic examination, due to the high prevalence's of ocular anomalies in these groups. Our review confirms the high prevalence of ocular anomalies in patients with unicoronal and lamdoid craniosynostosis. Moreover, in patients with metopic craniosynostosis we showed a high prevalence of astigmatism, which may lead to amblyopia left untreated.
Furthermore, a recent retrospective study of Hinds et al., 2021 examined 165 patients with syndromic craniosynostosis, in which they analyzed the first and last ophthalmic examination [44]. In regard to the visual acuity, 76.7% of these patients had a best corrected visual acuity (BVCA) better than 0.3 LogMAR at their last examination, which can have a positive impact on the normal functioning of these patients. The study of Hinds et al., 2021 is a follow-up study of Khan et al., 2003, and both studies advise early screening and identification of ocular anomalies in syndromic craniosynostosis, irrespective if there are any ocular signs or complaints [43,44].
Systematic reviews describing a rare disease generally have limitations, which also applies to our study. The first limitation was the difference in sample size of the included studies, namely this ranged between 5-205, which results in different prevalence's in regard to ophthalmic outcomes. In addition, the different types of craniosynostosis were often compared together, instead of individually, which makes it difficult to give an accurate prevalence of each ophthalmic outcome in each type of craniosynostosis. Furthermore, studies did not include healthy control groups to compare their study population with. Secondly, the method of ophthalmic examination and diagnosis, patient sample, in-and exclusion criteria were inconsistent in multiple studies. Assessment of ocular anomalies in children can be challenging, based on the accuracy and experience of the examiner. We expect that this might led to differences between the reported prevalence's for each outcome. Thirdly, the focus of each study with regard to ophthalmic outcomes, was not the same between most papers, therefore, not all ophthalmic abnormalities were reported by every study. This led to missing data in the calculation of an average prevalence, and therefore, the calculated prevalence is not as accurate, as it would have been if more studies reported the same outcomes. For example, only one study reported dysfunction in lacrimal system in syndromic craniosynostosis, and only two papers reported this outcome for non-syndromic craniosynostosis, due to these small numbers, no generalized statement can be made for these ocular conditions. Finally, the GRADE certainty rating was assessed as moderate, due to the small number of studies and sample sizes and relatively high heterogeneity between the studies. This systematic review shows the high occurrence of ocular anomalies in craniosynostosis. The aim of this review was to create awareness for the most prevalent ocular anomalies in a systematic order based on the two domains (1) anatomic ophthalmic domain and (2) functional ophthalmic domain. It is important to present this data on a well-organized and structured manner, so we can use this information to put more focus on finding a solution for optimal referral, screening, diagnosis, providing the required treatment and to develop new protocols. Based on the high occurrence of ocular anomalies in craniosynostosis as shown in our review, and based on the two recent studies on non-syndromic [38] and syndromic craniosynostosis [44], we can conclude that it is important to identify, screen and provide the necessary treatment to prevent any vision loss. However, no clear conclusion can yet be drawn at which age, each different type of disorders should be screened, by which technique. Future studies are needed, in which the ophthalmic conditions are examined in a prospective matter by an experienced orthoptist or ophthalmologist to prevent any performance bias. Furthermore, studies should include larger study samples, including multicenter studies (preferably internationally) to give more accurate data.